Nature agingPub Date : 2025-04-01Epub Date: 2025-02-19DOI: 10.1038/s43587-025-00813-5
Yun-Hee Youm, Christy Gliniak, Yuan Zhang, Tamara Dlugos, Philipp E Scherer, Vishwa Deep Dixit
{"title":"Enhanced paracrine action of FGF21 in stromal cells delays thymic aging.","authors":"Yun-Hee Youm, Christy Gliniak, Yuan Zhang, Tamara Dlugos, Philipp E Scherer, Vishwa Deep Dixit","doi":"10.1038/s43587-025-00813-5","DOIUrl":"10.1038/s43587-025-00813-5","url":null,"abstract":"<p><p>Age-related thymic involution precedes aging of all other organs in vertebrates and initiates the process of declining T cell diversity, which leads to eventual immune dysfunction. Whether FGF21, a liver-derived pro-longevity hormone that is also produced in thymic stroma, including by adipocytes, controls the mechanism of thymic demise is incompletely understood. Here, we demonstrate that elevation of FGF21 in thymic epithelial cells (TECs) and in adipocytes protects against thymic aging, whereas conditional hepatic overexpression did not impact thymic biology in aged mice. Notably, elevation of thymic FGF21 increased naïve CD8 T cells in aged animals and extended healthspan. Mechanistically, thymic FGF21 overexpression elevated TECs and reduced fibroadipogenic cells. Ablation of β-klotho, the obligatory co-receptor for FGF21 in Foxn1<sup>+</sup> TECs, accelerated thymic aging, suggesting regulation of TECs by FGF21 is partially required for thymic lymphopoiesis. These findings establish that paracrine FGF21 improves thymic function and delays immune aging.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"576-587"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-04-01DOI: 10.1038/s43587-025-00832-2
Nir Barzilai, Risa Starr, Eric Verdin, Laura J Niedernhofer, André Bertram, Gordon J Lithgow, Andrea B Maier
{"title":"Accelerating the promise of geroscience through The Academy of Health & Lifespan Research.","authors":"Nir Barzilai, Risa Starr, Eric Verdin, Laura J Niedernhofer, André Bertram, Gordon J Lithgow, Andrea B Maier","doi":"10.1038/s43587-025-00832-2","DOIUrl":"10.1038/s43587-025-00832-2","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"529-531"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-04-01Epub Date: 2025-03-31DOI: 10.1038/s43587-025-00840-2
Dongeun Heo, Anya A Kim, Björn Neumann, Valerie N Doze, Yu Kang T Xu, Yevgeniya A Mironova, Jared Slosberg, Loyal A Goff, Robin J M Franklin, Dwight E Bergles
{"title":"Transcriptional profiles of mouse oligodendrocyte precursor cells across the lifespan.","authors":"Dongeun Heo, Anya A Kim, Björn Neumann, Valerie N Doze, Yu Kang T Xu, Yevgeniya A Mironova, Jared Slosberg, Loyal A Goff, Robin J M Franklin, Dwight E Bergles","doi":"10.1038/s43587-025-00840-2","DOIUrl":"10.1038/s43587-025-00840-2","url":null,"abstract":"<p><p>Oligodendrocyte progenitor cells (OPCs) are highly dynamic, widely distributed glial cells of the central nervous system responsible for generating myelinating oligodendrocytes throughout life. However, the rates of OPC proliferation and differentiation decline dramatically with aging, which may impair homeostasis, remyelination and adaptive myelination during learning. To determine how aging influences OPCs, we generated a transgenic mouse line (Matn4-mEGFP) and performed single-cell RNA sequencing, providing enhanced resolution of transcriptional changes during key transitions from quiescence to proliferation and differentiation across the lifespan. We found that aging induces distinct transcriptomic changes in OPCs in different states, including enhanced activation of HIF-1α and WNT pathways. Pharmacological inhibition of these pathways in aged OPCs was sufficient to increase their ability to differentiate in vitro. Ultimately, Matn4-mEGFP mouse line and the sequencing dataset of cortical OPCs across ages will help to define the molecular changes guiding OPC behavior in various physiological and pathological contexts.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"675-690"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-04-01DOI: 10.1038/s43587-025-00848-8
{"title":"Pathways that limit differentiation of oligodendrocyte progenitors in the aging brain.","authors":"","doi":"10.1038/s43587-025-00848-8","DOIUrl":"10.1038/s43587-025-00848-8","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"544-545"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Large-scale proteomic analyses of incident Parkinson's disease reveal new pathophysiological insights and potential biomarkers.","authors":"Yi-Han Gan, Ling-Zhi Ma, Yi Zhang, Jia You, Yu Guo, Yu He, Lin-Bo Wang, Xiao-Yu He, Yu-Zhu Li, Qiang Dong, Jian-Feng Feng, Wei Cheng, Jin-Tai Yu","doi":"10.1038/s43587-025-00818-0","DOIUrl":"10.1038/s43587-025-00818-0","url":null,"abstract":"<p><p>The early pathophysiology of Parkinson's disease (PD) is poorly understood. We analyzed 2,920 Olink-measured plasma proteins in 51,804 UK Biobank participants, identifying 859 incident PD cases after 14.45 years. We found 38 PD-related proteins, with six of the top ten validated in the Parkinson's Progression Markers Initiative (PPMI) cohort. ITGAV, HNMT and ITGAM showed consistent significant association (hazard ratio: 0.11-0.57, P = 6.90 × 10<sup>-24</sup> to 2.10 × 10<sup>-11</sup>). Lipid metabolism dysfunction was evident 15 years before PD onset, and levels of BAG3, HPGDS, ITGAV and PEPD continuously decreased before diagnosis. These proteins were linked to prodromal symptoms and brain measures. Mendelian randomization suggested ITGAM and EGFR as potential causes of PD. A predictive model using machine learning combined the top 16 proteins and demographics, achieving high accuracy for 5-year (area under the curve (AUC) = 0.887) and over-5-year PD prediction (AUC = 0.816), outperforming demographic-only models. It was externally validated in PPMI (AUC = 0.802). Our findings reveal early peripheral pathophysiological changes in PD crucial for developing early biomarkers and precision therapies.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"642-657"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-04-01DOI: 10.1038/s43587-025-00837-x
Dorsa Toghani, Sanika Gupte, Sharon Zeng, Elmir Mahammadov, Edie I Crosse, Negar Seyedhassantehrani, Christian Burns, David Gravano, Stefan Radtke, Hans-Peter Kiem, Sonia Rodriguez, Nadia Carlesso, Amogh Pradeep, Alexis Georgiades, Fabienne Lucas, Nicola K Wilson, Sarah J Kinston, Berthold Göttgens, Le Zong, Isabel Beerman, Bongsoo Park, Derek H Janssens, Daniel Jones, Ali Toghani, Claus Nerlov, Eric M Pietras, Marion Mesnieres, Christa Maes, Atsushi Kumanogoh, Thomas Worzfeld, Jin-Gyu Cheong, Steven Z Josefowicz, Peter Kharchenko, David T Scadden, Antonio Scialdone, Joel A Spencer, Lev Silberstein
{"title":"Author Correction: Niche-derived Semaphorin 4A safeguards functional identity of myeloid-biased hematopoietic stem cells.","authors":"Dorsa Toghani, Sanika Gupte, Sharon Zeng, Elmir Mahammadov, Edie I Crosse, Negar Seyedhassantehrani, Christian Burns, David Gravano, Stefan Radtke, Hans-Peter Kiem, Sonia Rodriguez, Nadia Carlesso, Amogh Pradeep, Alexis Georgiades, Fabienne Lucas, Nicola K Wilson, Sarah J Kinston, Berthold Göttgens, Le Zong, Isabel Beerman, Bongsoo Park, Derek H Janssens, Daniel Jones, Ali Toghani, Claus Nerlov, Eric M Pietras, Marion Mesnieres, Christa Maes, Atsushi Kumanogoh, Thomas Worzfeld, Jin-Gyu Cheong, Steven Z Josefowicz, Peter Kharchenko, David T Scadden, Antonio Scialdone, Joel A Spencer, Lev Silberstein","doi":"10.1038/s43587-025-00837-x","DOIUrl":"10.1038/s43587-025-00837-x","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"720"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-04-01DOI: 10.1038/s43587-025-00838-w
Erik Jacques, Chiara Herzog, Kejun Ying, Alan Tomusiak, Jessica Kasamoto, Raghav Sehgal, Seth Paulson, Julian Reinhard, Jakob Träuble, Waylon J Hastings, Alexander Tyshkovskiy, Sara Hägg, John C Earls, Christian E Behrens, Jessica Lasky-Su, Gavin Zhou, Eric Morgen, John S Tsang, Riccardo E Marioni, Xiao-Jun Ma, Alexandra Stolzing, Christin Glorioso, Jonathan S Gootenberg, Omar O Abudayyeh, M Austin Argentieri, Raymond H Mak, Lynne S Cox, Andrew S Brack, Gordan Lauc, David Furman, Jason D Buenrostro, Björn Schumacher, Jamie N Justice, Tina Woods, David Gobel, Viviana I Perez, David A Sinclair, Andrea B Maier, Nir Barzilai, Michael P Snyder, Tony Wyss-Coray, Steve Horvath, Luigi Ferrucci, Jesse R Poganik, Mahdi Moqri, Vadim N Gladyshev
{"title":"Invigorating discovery and clinical translation of aging biomarkers.","authors":"Erik Jacques, Chiara Herzog, Kejun Ying, Alan Tomusiak, Jessica Kasamoto, Raghav Sehgal, Seth Paulson, Julian Reinhard, Jakob Träuble, Waylon J Hastings, Alexander Tyshkovskiy, Sara Hägg, John C Earls, Christian E Behrens, Jessica Lasky-Su, Gavin Zhou, Eric Morgen, John S Tsang, Riccardo E Marioni, Xiao-Jun Ma, Alexandra Stolzing, Christin Glorioso, Jonathan S Gootenberg, Omar O Abudayyeh, M Austin Argentieri, Raymond H Mak, Lynne S Cox, Andrew S Brack, Gordan Lauc, David Furman, Jason D Buenrostro, Björn Schumacher, Jamie N Justice, Tina Woods, David Gobel, Viviana I Perez, David A Sinclair, Andrea B Maier, Nir Barzilai, Michael P Snyder, Tony Wyss-Coray, Steve Horvath, Luigi Ferrucci, Jesse R Poganik, Mahdi Moqri, Vadim N Gladyshev","doi":"10.1038/s43587-025-00838-w","DOIUrl":"10.1038/s43587-025-00838-w","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"539-543"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-04-01DOI: 10.1038/s43587-025-00839-9
Ghita Ghislat, Inmaculada Tasset
{"title":"The Women In Autophagy network empowers global equity in science.","authors":"Ghita Ghislat, Inmaculada Tasset","doi":"10.1038/s43587-025-00839-9","DOIUrl":"10.1038/s43587-025-00839-9","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"532-533"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-04-01Epub Date: 2025-02-05DOI: 10.1038/s43587-024-00799-6
Rabia R Khawaja, Adrián Martín-Segura, Olaya Santiago-Fernández, Rebecca Sereda, Kristen Lindenau, Mericka McCabe, Adrián Macho-González, Maryam Jafari, Aurora Scrivo, Raquel Gomez-Sintes, Bhakti Chavda, Ana Rosa Saez-Ibanez, Inmaculada Tasset, Esperanza Arias, Xianhong Xie, Mimi Kim, Susmita Kaushik, Ana Maria Cuervo
{"title":"Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging.","authors":"Rabia R Khawaja, Adrián Martín-Segura, Olaya Santiago-Fernández, Rebecca Sereda, Kristen Lindenau, Mericka McCabe, Adrián Macho-González, Maryam Jafari, Aurora Scrivo, Raquel Gomez-Sintes, Bhakti Chavda, Ana Rosa Saez-Ibanez, Inmaculada Tasset, Esperanza Arias, Xianhong Xie, Mimi Kim, Susmita Kaushik, Ana Maria Cuervo","doi":"10.1038/s43587-024-00799-6","DOIUrl":"10.1038/s43587-024-00799-6","url":null,"abstract":"<p><p>Aging leads to progressive decline in organ and tissue integrity and function, partly due to loss of proteostasis and autophagy malfunctioning. A decrease with age in chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation, has been reported in various organs and cells from rodents and humans. Disruption of CMA recapitulates features of aging, whereas activating CMA in mice protects against age-related diseases such as Alzheimer's, retinal degeneration and/or atherosclerosis. However, sex-specific and cell-type-specific differences in CMA with aging remain unexplored. Here, using CMA reporter mice and single-cell transcriptomic data, we report that most organs and cell types show CMA decline with age, with males exhibiting a greater decline with aging. Reduced CMA is often associated with fewer lysosomes competent for CMA. Transcriptional downregulation of CMA genes may further contribute to CMA decline, especially in males. These findings suggest that CMA differences may influence organ vulnerability to age-related degeneration.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"691-708"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-04-01Epub Date: 2025-03-05DOI: 10.1038/s43587-025-00819-z
Wenchao Li, Zhenhua Zhang, Saumya Kumar, Javier Botey-Bataller, Martijn Zoodsma, Ali Ehsani, Qiuyao Zhan, Ahmed Alaswad, Liang Zhou, Inge Grondman, Valerie Koeken, Jian Yang, Gang Wang, Sonja Volland, Tania O Crişan, Leo A B Joosten, Thomas Illig, Cheng-Jian Xu, Mihai G Netea, Yang Li
{"title":"Single-cell immune aging clocks reveal inter-individual heterogeneity during infection and vaccination.","authors":"Wenchao Li, Zhenhua Zhang, Saumya Kumar, Javier Botey-Bataller, Martijn Zoodsma, Ali Ehsani, Qiuyao Zhan, Ahmed Alaswad, Liang Zhou, Inge Grondman, Valerie Koeken, Jian Yang, Gang Wang, Sonja Volland, Tania O Crişan, Leo A B Joosten, Thomas Illig, Cheng-Jian Xu, Mihai G Netea, Yang Li","doi":"10.1038/s43587-025-00819-z","DOIUrl":"10.1038/s43587-025-00819-z","url":null,"abstract":"<p><p>Aging affects human immune system functionality, increasing susceptibility to immune-mediated diseases. While gene expression programs accurately reflect immune function, their relationship with biological immune aging and health status remains unclear. Here we developed robust, cell-type-specific aging clocks (sc-ImmuAging) for the myeloid and lymphoid immune cell populations in circulation within peripheral blood mononuclear cells, using single-cell RNA-sequencing data from 1,081 healthy individuals aged from 18 to 97 years. Application of sc-ImmuAging to transcriptome data of patients with COVID-19 revealed notable age acceleration in monocytes, which decreased during recovery. Furthermore, inter-individual variations in immune aging induced by vaccination were identified, with individuals exhibiting elevated baseline interferon response genes showing age rejuvenation in CD8<sup>+</sup> T cells after BCG vaccination. sc-ImmuAging provides a powerful tool for decoding immune aging dynamics, offering insights into age-related immune alterations and potential interventions to promote healthy aging.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"607-621"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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